This invention relates to receptor proteins.
The retinoid X receptors (RXRs) are members of a large superfamily of intracellular hormone receptors. These proteins bind to specific DNA sequences and directly regulate transcription of target genes in response to activation by their specific ligands (Leid et al., Trends Biochem. Sci. 17:427-433, 1992; Leid et al., Cell 68:377-395, 1992; Mangelsdorf et al., Nature 345:224-229, 1990 and Yu et al., Cell 67:1251-1266, 1991). The RXRs belong to a large subgroup of the superfamily defined by a conserved subregion within the DNA binding domain. This group also includes the receptors for retinoic acid, thyroid hormone, and vitamin D as well as a number of other less well characterized proteins, called orphan receptors, that do not have known ligands. As monomers, the members of this class can bind to sequences related to the hexameric consensus AGGTCA. RXR homodimers bind to tandem repeats of this consensus separated by a single base pair (Manglesdorf et al., Cell 66:555-561, 1991), and apparently to additional elements including .beta.-RARE (Zhang et al., Nature 358:587-591, 1992). These homodimer binding sites confer specific response to 9-cis-RA (9-cis-RA), the ligand for the RXRs. In addition, the RXRs heterodimerize with a variety of other family members, including the receptors for all- trans-retinoic acid, thyroid hormone (T3), and vitamin D. This heterodimerization strongly increases the affinity of these receptors for their specific response elements (Yu et al., Cell 67:1251-1266, 1991; Zhang et al., Nature 358:587-591, 1992; Bugge et al., EMBO J. 11:1409-1418, 1992), and recent evidence also demonstrates that it is also required for full hormone dependent transcriptional activity of at least the thyroid hormone receptor-RXR complex.
Mammals have three genes encoding .alpha., .beta., and .gamma. isoforms of RXR (Mangelsdorf et al., Genes & Dev. 6:329-344, 1992). The expression patterns of murine RXRs (Mangelsdorf et al., Genes & Dev. 6:329-344, 1992) and homologues of RXR found in Xenopus (Blumberg et al., Proc. Natl. Acad. Sci. USA 89:2321-2325, 1992) and Drosophila (Oro et al., Nature 347:298-301, 1990) suggest that the members of the RXR family play important roles in several aspects of development and central nervous system differentiation as well as in adult physiology. Based on both their specific response to the 9-cis-RA metabolite and their heterodimerization with the RARs, it is clear that the RXRs play a central role in the broad regulatory effects of retinoids. Moreover, their heterodimeric interactions with other family members indicate that the RXRs also play a central role in response to thyroid hormone, vitamin D, and perhaps other compounds. This dual function is unique within the nuclear receptor superfamily.